tbuckley/cabot-search huggingface dataset:
The emerging use of immunotherapy as a treatment option in metastatic renal cell carcinoma: Real-world evidence from a single UK tertiary cancer centre.
Authors: Justin KH Liu, Andrew F. Irvine, Mustafa Altarqane, Mariyam Arif, Vikram Bansal, Anne Boyle, Fiona C Campbell, Noha Elsayed, Mdehteshamul E. Hafiz, Ashraful Huda, Aye Soe, Anthony Maraveyas, John McGrane, Iqtedar A Muazzam
Journal: Journal of Clinical Oncology (2023)

e16509 Background: The landscape of systemic anticancer therapy (SACT) options for the treatment of metastatic renal cell carcinoma (mRCC) has recently evolved following results from the CheckMate 214 trial in 2018 which demonstrated improved overall survival in patients with International mRCC Database Consortium (IMDC) intermediate- and poor-risk mRCC clear cell histological subtype receiving combination immunotherapy (Ipilimumab/Nivolumab) in the first-line setting compared to Sunitinib. This is in addition to other treatment options including: vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) (e.g. Sunitinib, Pazopanib, Tivozanib, Cabozantinib, etc.), combination immunotherapy/TKI (e.g. Avelumab/Axitinib), VEGF/mammalian target of Rapamycin (mTOR) inhibitors (e.g. Lenvatinib/Everolimus) and single-agent immunotherapy (e.g. Nivolumab) in both first- and second-line settings. Methods: An audit of SACT prescribing practices in mRCC between 2019-2022 in a single UK tertiary cancer centre (Castle Hill Hospital, Hull, UK) was conducted as part of a national collaboration multi-centre UK audit looking into the real-world landscape and treatment choices in mRCC. Information was derived from the Somerset Cancer Registry and a dataset containing 87 patients with a coded diagnosis of ‘malignant neoplasm of kidney, except renal pelvis (CX64X)’ and ‘secondary malignant neoplasm of kidney &amp; renal pelvis (C790)’ was generated. Results: Of the 81 patients included in the final analysis, 65% (n = 53) were male and 81% (n = 66) had a clear cell histological subtype. The main sites of metastases were lung (n = 58) and lymph nodes (n = 45). Most of the patients (n = 72) received either one or two lines of SACT. Of those with clear cell mRCC, 74% (n = 51/69) were classed as having IMDC intermediate- or poor-risk features with almost half (n = 34/69) receiving combination Ipilimumab/Nivolumab. Comparing overall survival (OS) and progression-free survival (PFS) to the published Kaplan-Meier curves in the CheckMate 214 trial, no significant differences in OS (p = 0.6) and PFS (p = 0.13) were observed, although there was an overall trend towards improved PFS in the first 6 months (82.4% vs 63.3%) in our local dataset. Conclusions: The results of our real-world evaluation of prescribing practices in mRCC favoured the use of combination immunotherapy in the first-line setting for the treatment of IMDC intermediate- and poor-risk clear cell mRCC with similar outcomes to the published data in the CheckMate 214 trial. The overall trend towards improved PFS in the first 6 months in our local dataset highlights the importance of patient selection when using immunotherapy.
OS analysis of patients with different short-term response and progression patterns of donafenib versus sorafenib as first-line therapy for advanced hepatocellular carcinoma: An exploratory subgroup analysis of ZGDH3.
Authors: Shukui Qin, Feng Bi, Jianming Xu, Chengyou Du, Qingxia Fan, Longzhen Zhang, Min Tao, Da Jiang, Senming Wang, Yongping Chen, Jifang Sheng, Xuelong Zhuang, Jun Wu
Journal: Journal of Clinical Oncology (2023)

e16143 Background: Donafenib, a deuterated derivative of sorafenib, significantly prolonged overall survival (OS) in patients with advanced hepatocellular carcinoma in an open, randomized, parallel-controlled phase II/III trial (ZGDH3) compared with sorafenib. The purpose of this study was to explore and analyse the OS benefits of donafenib and sorafenib treatment in patients with different short-term response and progression patterns. Methods: This analysis was based on the ITT population of ZGDH3 study (defined as all randomized patients). The median OS of donafenib and sorafenib was assessed by the Kaplan-Meier method and was compared according to different short-term response (SD, others) and progression patterns (intrahepatic lesion growth, intrahepatic new lesion, extrahepatic lesion growth, extrahepatic new lesion). The stratified Cox proportional hazard model was used to calculate the hazard ratio and its 95% confidence interval. Results: 668 patients were included in the analysis (334 in each group). Donafenib was associated with a trend of improved OS benefit when compared with sorafenib in most subgroups (HR &lt; 1), including best short-term response of SD or others, confirmed short-term response of SD or others, intrahepatic lesion growth or not, intrahepatic new lesion or not, extrahepatic new lesion or not, no extrahepatic lesion growth. The benefit was statistically significant in the following subgroups: in patients with response of SD, the mOS of donafenib and sorafenib were 19.3 and 15.5 months, respectively (HR 0.714, 95%CI 0.550-0.928). Among patients with confirmed response of SD, the mOS was 29.0 and 22.8 months, respectively (HR 0.641, 95% CI 0.418-0.983). Among patients without extrahepatic lesion growth (defined as lesion growth ≥20% from baseline), the mOS was 12.6 months and 10.0 months, respectively (HR 0.783, 95% CI 0.648-0.945). Among patients without new extrahepatic lesions, the mOS was 13.1 months and 11.0 months (HR 0.816, 95% CI 0.677-0.998), respectively. Conclusions: Donafenib exhibited better survival benefit than sorafenib in most subgroups, especially in patients with the best response and confirmed best response of SD, which further confirmed the excellent efficacy of donafenib in first-line treatment of advanced HCC. Clinical trial information: NCT02645981 . [Table: see text]
Randomized phase III trial in MMR deficient (MMRd) endometrial cancer (EC) patients comparing chemotherapy (CT) alone versus dostarlimab in first line advanced/metastatic setting: DOMENICA study (GINECO-EN105b/ENGOT-en13 study).
Authors: Florence Joly, Isabelle Laure Ray-Coquard, Maria Jesus Rubio, Xavier Paoletti, Alison J. Davis, Emma Hudson, Domenica Lorusso, Germana Tognon, Ursula Hasler-Strub, Chel Hun Choi, Mehmet Ali Vardar, Stephanie Lheureux, Toon Van Gorp, David Shao Peng Tan, Fabian Trillsch, Lauriane Eberst, Céline Lescure, Anne-Claire Hardy-Bessard, Marie Chaix
Journal: Journal of Clinical Oncology (2023)

TPS5630 Background: The standard treatment for advanced EC is still platinum-based combination CT, regardless of the histology, molecular status and the patient’s profile. However, EC patients are a particularly frail group of patients, often with co-morbidities. Tolerance of CT can be difficult and induce long-term toxicities. In advanced EC disease, MMRd/MSI-H tumors represent 15 to 20 % of cases. Preclinical data suggest that these tumors are more resistant to platinum. On the other hand, anti-PD1 immunotherapy has shown impressive results among MMRd/MSI-H EC patients after platinum-based CT. The aim of this study is to de-escalade the first line advanced/metastatic treatment of patients with MMRd/MSI-H endometrial cancer with the objective to avoid carboplatin-paclitaxel related toxicities by substituting CT with the PD1 inhibitor dostarlimab. Methods: DOMENICA is an ongoing international randomized, open-label, phase III trial. 142 patients with MMRd/MSI-H EC Stage III or Stage IV or first recurrent disease without curative treatment (surgery, radiation therapy, +/- adjuvant CT) will be randomized (1:1) to receive either 4 cycles of dostarlimab 500mg every 3 weeks followed by dostarlimab 1000mg every 6 weeks as maintenance up to 2 years or 6 cycles of carboplatin-paclitaxel. A cross over is allowed from the CT arm to the dostarlimab arm at first progression. The maximum treatment duration with dostarlimab will be 24 months. Stratification factors are prior adjuvant CT, prior pelvic radiotherapy. The primary endpoint is the progression-free survival (PFS). Secondary endpoints include overall survival (OS), PFS2, quality of life, best objective response rate, disease control rate, duration of response rate, safety, tolerability, time to first and second subsequent therapy, efficacy of second systemic therapies, pharmacokinetics description and immunogenicity determination. The study is designed to expect a 17.8-months PFS in dostarlimab arm and a 10-months PFS in the CT arm, translating to a hazard ratio of 0.58. A protocol amendment is submitted to increase patient population (with extended eligibility criteria, PFS hypothesis). Status: The DOMENICA/GINECO-EN105b/ENGOT-en13 trial is currently recruiting, the first patient was randomized in April 2022. Clinical trial information: NCT05201547 .
Study on the mechanism of CXCR3 expression in paracancer and tumor tissues of colon cancer patients.
Authors: Xiaoming Wang, Sen Wang, Yangyang Zhang, Hongyan Ni, Benling Xu, Peng Zhao, Guangyu Chen, Long Yuan
Journal: Journal of Clinical Oncology (2023)

e15506 Background: Colorectal cancer (CRC) is one of the most common types of malignant tumors, and its incidence is increasing year by year.Chemokines are small cytokines or signaling proteins secreted by cells. They have the ability to induce directional chemotactic migration of nearby responding cells and can mediate intracellular signal transduction by binding to 18 G protein-coupled receptor families.C-X-C motif chemokine receptor 3 (CXCR3) is activated by three Interferon-γ inducible ligands CXCL9, CXCL10 and CXCL11 and encodes 368 amino acids. Its molecular weight was about 41KDa and the cDNA was 1104bp in length.In recent years, a large number of studies have confirmed that the expression of CXCR3 and its ligands in the body is closely related to tumor immunity, tumorigenesis and metastasis.Therefore, the aim of this study is to investigate the expression of CXCR3 in tumor and adjacent intestinal tissues of patients with colorectal cancer and the effects of related gene detection on tumor proliferation, migration, invasion and recurrence in patients with colorectal cancer. Methods: Flow cytometry was used to detect 40 colon cancer patients who had not received neoadjuvant therapy in the Department of General Surgery of the Affiliated Cancer Hospital of Zhengzhou University. The expression of CXCR3, PD-1, CD4+, CD45+ and CD8+T cells in tumor and para-tumor specimens (taken &gt; 2cm from the edge of the cancer) was detected, and the expression characteristics of CXCR3 in colon cancer patients and its correlation with general clinical data were analyzed. The correlation between KRAS, MSS, MSI-H gene mutations and colon cancer was analyzed under the condition of different lymphocyte expression. Results: 1.CXCR3+CD8+T cells were significantly different, and CXCR3+CD4+T cells were significantly different. These results suggest that CXCR3 expression with different lymphocytes may play an important role in tumor cell growth.2.The difference of CD45+T cells was statistically significant. This suggests that the expression of CD45+T cells may also affect tumor growth.3.CXCR3+CD4+T cells may play a role in promoting tumor metastasis. Conclusions: The expression of CXCR3+CD8+T cells, CXCR3+CD4+T cells and CD45+T lymphocytes in tumor tissues of colon cancer patients is correlated with the expression of adjacent tissues. The expression of PD-1+CD8+ lymphocytes in tumor tissues is less than that in adjacent tissues, indicating that they are related to tumor metastasis and proliferation. CXCR3 may play an important role in lymph node metastasis, and PD-1 expression may also be related to patient gender. Therefore, the expression of CXCR3 and T lymphocytes in tumor tissues and adjacent tissues of patients is helpful for the diagnosis and treatment of colon cancer, and has important value in clinical application.
Augmented curation of disease diagnoses and medications for patients with hepatocellular carcinoma.
Authors: Wui Ip, Colin Pawlowski, Vineet Mathew, Mayank Choudhary, Michiel Niesen, Akash Anand, Allen Mao, Ananth Peddinti, Chetan Kancharla, Isaac Kunz, Joseph D. Bonner, Matthew Boyle, Olamilekan Jinadu, Alex Pozhitkov, Xiaoyu Xia, Raul Sarmiento, Stacy Berger, Tarrah Kirkpatrick, Venky Soundararajan, Samir Courdy
Journal: Journal of Clinical Oncology (2023)

e13573 Background: Unstructured EHR data contains nuanced rich insights for Real World Evidence (RWE) studies, however harnessing this unstructured data at scale can be challenging. Here, we evaluated two Natural Language Processing-based curation (“augmented curation”) models to identify medical conditions and medications from clinical notes for patients with hepatocellular carcinoma at City of Hope National Medical Center. Methods: We deployed two augmented curation models originally trained on de-identified EHR data from the nference nSights platform, a federated data platform comprising clinical data from several Academic Medical Centers, on clinical notes found in the City of Hope POSEIDON platform, an oncology insights engine. We assessed their performances using manual chart review as reference. We then calculated an Enrichment Factor (EF) score for augmented curation model extraction and its 95% confidence intervals. The EF score was defined as the number of patients captured by either augmented curation or structured data divided by the number of patients captured by structured data alone. Results: The augmented curation models captured conditions and medications from clinical notes with F1 scores of 0.93 and 0.95, respectively. Compared to structured EHR data alone, the disease diagnosis model captured significantly more individuals with signs and symptoms such as vomiting (EF: 22.8, 95% CI: [15.2, 41.1]), weight loss (EF: 5.0, 95% CI: [4.1, 6.6]), nausea (EF: 4.3, 95% CI: [3.1, 6.9]), and edema (EF: 3.1, 95% CI: [2.7, 3.7]). Similarly, the medication use augmented curation model captured significantly more individuals with medications such as interferon, aspirin, and pembrolizumab. From a Cox proportional hazards model analysis, we found that a survival model using augmented curation-based features and structured data achieved a model concordance of 0.745 (95% CI: [0.741, 0.748]), compared to 0.722 (95% CI: [0.717, 0.726]) for the model based on structured data alone. In addition, the augmented curation-based survival model identified jaundice (HR: 2.0, 95% CI: [1.5, 2.7]) as a significant risk factor for mortality, which was not picked up by the structured data-based survival model. Conclusions: Overall, this study shows that augmented curation models can be used to accurately capture comorbidities and medications from unstructured clinical notes, and these extracted covariates are correlated with clinically meaningful endpoints such as survival. We recommend using augmented curation as a standard insight generation approach in RWE study protocols.
Real world outcomes of next generation sequencing (NGS) of progressive RAI resistant metastatic thyroid cancer and treatment of these patients with redifferentiation protocol.
Authors: Jennifer Wheeley, Nikita Chintapally, Kanchan Kulkarni, Reshmi Nair, Priya Kundra, Jennifer Rosen, Meeta Sharma, Jason Wexler, Kenneth D Burman, Leila Shobab, Irina Veytsman
Journal: Journal of Clinical Oncology (2023)

e18088 Background: Patients with papillary and follicular thyroid cancer (PTC and FTC) who are refractory to radioactive iodine treatment (RAIR) have poor prognosis. Frequently these patients are found to have BRAF V600E and NRAS Q61R mutations, which can be targeted using BRAF and MEK inhibitors to promote redifferentiation of thyroid cancer (TC) cells to take up RAI. The aim of this study is to define clinical, pathological, and molecular characteristics associated with response to redifferentiation therapy. Methods: NGS was performed to identify targetable mutations. The protocol consisted of 6 weeks of either dual therapy Trametinib and Dabrafenib (BRAF V600E) or Trametinib alone (NRAS Q61R) followed by dosimetry and therapeutic RAI administration. Interim imaging and biochemical analysis were performed at 3 months and 6 months. Statistical analysis was performed using the Kaplan-Meier survival analysis to estimate the mean time to progression from the protocol finish date. Patients who did not progress were censored at the last date of their clinic visit or at 192 days. Exploratory analysis was conducted to look at the change in trends in thyroglobulin (TG) values. Results: 16 patients met eligibility criteria. Previous RAI dosage ranged from 83mCi to 700mCi of Iodine 131 (I-131). 5 patients were African American, and 1 was Hispanic. Upon molecular analysis, 11 patients were found to have BRAF V600E mutation, 4 patients had NRAS Q61R mutation, and 1 was not identified. All but one patient had RAI uptake and received a dosage of 140 – 357 mCi of I-131 after dosimetry scan calculation. Upon interim analysis, 3 patients progressed at 3 months and an additional 3 patients progressed at 192 days. At 192 days, the mean time to progression from protocol finish date was 170 days (SD=9.7). Interim TG level analysis and images analysis are reflected in the table. There were other mutations identified: 11 patients were PDL1 negative, 5 PDL1 positive with range of 1-50%, 8 with TERT mutation, 4 with TP53, 2 with CHEK 2, other mutations were DNMT3A, FGFR3, BLM, EGFR, GNAS, ARID1, PDGFRA, NFE2L2, ARID2, Exon 17, POT1 Exon 14, and NTRK, were only present in one patient each. Conclusions: All but one patient with RAIR TC with BRAF V600E or NRASQ61R mutation who have undergone redifferentiation protocol have increased uptake of RAI after 6 weeks of targeted therapy with excellent response on interim analysis. Our study is ongoing to further define clinical, pathological, and molecular characteristics that help select patients with advanced TC who benefit most from redifferentiation treatment. Clinical trial information: 00005381 . [Table: see text]
Targeting CD47 in lymphoid malignancies with CAR T cells.
Authors: Alexander Paul Boardman, Scott James, Marcel R. M. Van Den Brink
Journal: Journal of Clinical Oncology (2023)

2513 Background: Despite major therapeutic advances of chimeric antigen receptor (CAR) T cells directed against CD19 in relapsed and refractory non-Hodgkin lymphoma (NHL), two thirds of patients experience relapse within the first two years. Nearly one third of these relapses are associated with CD19 antigen-loss escape thus leveraging alternate CAR targets may improve outcomes. CD47, an anti-phagocytic “don’t eat me” receptor known to be overexpressed in NHL, is an ideal CAR target as it is potentially indispensable for tumor progression. Methods: CD47-CAR binding domains were engineered either as a camelid single variable heavy chain nanobody (CD47-VHH-CAR) or as the CD47 binding domain of cognate receptor SIRPα (SIRPα-CAR), each combined with a CD28 costimulatory domain and a CD3ζ activation domain with two mutated ITAMs (1XX). In vitro co-culture assays were performed with lymphoid mouse tumor cell lines BM185 and A20. For in vivo experiments, syngeneic BALB/c mice were sublethally irradiated for lymphodepletion then injected intravenously with 1x10 5 luciferase + BM185 cells. Two days later, mice were injected with 2x10 6 CAR T cells, and bioluminescence imaging was performed to monitor tumor progression. For bio-localization experiments, CAR T cells were co-transduced with a separate vector encoding luciferase. Results: CD47-CAR T cell expansion in vitro was hindered due to fratricide, which can be rescued by CD47 CRISPR knockout. Both CD47-VHH-CAR and SIRPa-CAR T cells exhibited potent and specific in vitro lysis of BM185 and A20 cells. CD47-VHH-CAR T cells showed transient anti-leukemia activity, however, survival was not significantly prolonged. T cell bio-localization analysis revealed that, compared to CD19-CAR T cells, CD47-VHH-CAR T cells exhibited prolonged retention in the thorax with minimal bone marrow trafficking, suggesting CD47 antigen-specific pulmonary sequestration, and inferior expansion. SIRPα-CAR T cells engineered to secrete pro-inflammatory cytokine IL-18 significantly improved CAR T cell expansion, resulting in bone marrow trafficking and clearance of BM185 tumor. However, recipients of IL-18-secreting SIRPa-CAR T cells experienced lethal CAR T cell-related toxicity. To improve the safety of CD47-CAR T cells, we engineered an NFAT-responsive vector expressing the CD47-CAR modified with E. coli-derived dihydrofolate reductase drug destabilization domain to limit CD47-CAR expression to T cells exposed to the stabilizing antibiotic trimethoprim and receiving a licensing NFAT signal from a CD19-CAR. Conclusions: In vivo activity of CD47-targeting CAR T cells is limited by thoracic retention and limited expansion, which can be partially overcome by overexpression of IL-18, though enhanced toxicity precludes survival prolongation. Our findings suggest that strategies to spatiotemporally restrict CAR expression or activation will be necessary to achieve safe and efficacious CD47-CAR T cell activity.
A prospective observational study investigating the impact of immune checkpoint inhibitors for cancer on fertility in males and females of child-bearing age (immuno-fertility).
Authors: Rachel J Keogh, David O'Reilly, Sam Jonathan Marks, Maebh Horan, Rachel Elebert, Louise Glover, Maciej Milewski, Keith Egan, Bryan T Hennessy, William Grogan, Patrick G. Morris, Oscar S. Breathnach, Adrian Gerard Murphy, Mary Wingfield, David A Crosby, Jarushka Naidoo
Journal: Journal of Clinical Oncology (2023)

TPS2679 Background: Anti-PD-1/PD-L1/CTLA4 agents have revolutionized the treatment landscape of many cancer types, resulting in durable responses. With recent approvals in the adjuvant setting, the long-term consequences of immune checkpoint inhibitors (ICIs) such as the impact on fertility are of increasing clinical relevance. The impact of ICI therapy on fertility is poorly understood. Based on published data, we hypothesize that patient fertility may be affected by ICIs via several mechanisms, including: endocrine dysfunction, direct impact on gametogenesis, or autoantibody formation. Methods: We designeda prospective, multi-center translational study that aims to identify the effects of ICIs on fertility. We aim to recruit 88 patients over 3-4 years. Participants of child-bearing age as defined by study protocol who are due to start ICIs for any solid tumour malignancy, will be eligible. The primary endpoint of the study is a change in anti-Müllerian hormone level and antral follicle count in females, and a change in sperm concentration, motility, morphology in males measured before and serially during ICI therapy (up to 24 months). Secondary endpoints include analysis of FSH, LH, testosterone levels, the proportion of patients with a persistent change in any one reproductive parameter as assessed at follow-up visits, frequency of oligo/amenorrhoea in females and immunologic changes in seminal fluid in males. Conclusions: ICIs have led to a significant improvement in the long-term survival in selected patients with cancer. This study will elucidate the effects of ICIs on both male and female fertility over time, and provide useful information to guide patients and their care teams regarding long-term effects of ICIs on fertility. Recruitment is ongoing.